The present invention relates to a novel method for preparing vitamin A and to novel intermediates obtained using this method.
It is known according to the patent application published under the number EP-A-0647623 to prepare vitamin A from ethynyl-retro-xcex1-ionol carbonate and 2-methylbutadiene followed by rearrangement into an allene derivative in the presence of a rearrangement catalyst chosen from nickel and/or palladium in the presence of a phosphine. The last step consists in isomerizing the product obtained in the preceding step to retinal. This method has several disadvantages from the industrial point of view; on the one hand, the preparation in the first step of a carbonate whose preparation yield is not excellent and, on the other hand, the second step has rearrangement yields which are not excellent either and requires the use of an expensive rearrangement catalyst which makes the method difficult to exploit industrially.
The present invention has made it possible, starting with ethynyl-retro-xcex1-ionol, to directly obtain an allene derivative without preparing the carbonate intermediate. This reaction is carried out in the presence of a metal catalyst.
It is known in the prior art, for example according to patents FR 1 554 805 and FR 2 135 550, to carry out the isomerization of propargyl alcohols to xcex1,xcex2-ethylenic aldehydes using either catalysts based on alkyl orthovanadates or silyl orthovanadates. Unfortunately, this type of catalyst has no action on ethynyl-retro-xcex1-ionol.
The present invention relates to the preparation of a C15 intermediate of vitamin A of formula: 
where, in a first step, the ethynyl-retro-xcex1-ionol is acetylated, in a second step, the ethynyl-retro-xcex1-ionol acetate is isomerized to allene acetate and in a final step, the compound obtained in the second step is hydrolyzed. The first step may be schematically represented in the following manner: 
The preparation of propargyl acetate is carried out by bringing ethynyl-retro-xcex1-ionol into contact with acetic anhydride or acetyl chloride in the presence of a tertiary amine. Triethylamine, trimethylamine, tributylamine or pyridine is preferably used as tertiary amine. An activating agent such as dimethylaminopyridine is preferably added. The quantity of activating agent which is used is preferably between 1 and 5%, calculated in molar equivalent relative to the alcohol. It is preferable to work in an inert solvent which is chosen in particular from optionally halogenated aromatic or aliphatic solvents.
The second step, which consists in isomerizing the propargyl acetate obtained in the receding step, is carried out in the presence of a copper-based metal catalyst according to the following reaction scheme: 
The catalysts used in the prior art and in particular in patent EP-A-0 647 623 based on palladium and/or on nickel, which-allow the formation of allenes from carbonates, are not active in the context of the present invention or give a completely degraded reaction mixture.
The use of copper(I) chloride is preferred.
For a better implementation of the invention, a molar ratio of copper(I) salt to propargyl acetate of between 0.5% and 5%, and preferably of about 1% is used. The reaction solvent is preferably chosen from the optionally halogenated aromatic or aliphatic solvents and esters. Monochlorobenzene is preferably used.
The optimum concentration of propargyl acetate in the reaction solvent is between 0.1 and 1 mol per liter and more preferably about 0.5 mol per liter.
The temperature conditions are chosen within limits which do not cause degradation of the propargyl acetate. It is preferable to work at temperatures of between 100 and 150xc2x0 C. and preferably at about 100xc2x0 C.
The allene intermediate of the following formula is a novel compound: 
The next step consists in hydrolyzing the allene acetate to the corresponding aldehyde according to the following reaction: 
This reaction is carried out in the presence of an acid in a ketone solvent or in an aromatic solvent which is in particular halogenated. The isomerization and deacetylation catalyst is an inorganic acid chosen in particular from hydrochloric acid, hydrobromic acid or sulfuric acid. The use of hydrobromic acid in acetone is preferred.
According to a better way of carrying out the invention, the use of 0.25 to 0.5 equivalent of hydrobromic acid per mol of allene acetate is preferred.
Starting with the C15 aldehyde obtained in the preceding step, vitamin A is prepared according to a known method. There may be mentioned among the known methods patent FR 2,707,633 which, by condensation with a lithium or potassium salt of prenal dienolate, makes it possible to obtain a dihydropyran intermediate which, by controlled hydrolysis in the presence of a weak acid, leads to retinal.
It is also known according to the article by Krasnaya and Kucherov which appeared in Izvestiya Akademii Nauk SSSr, Otdelenie Khimicheskikh Nauk, No 6, pp 1160-1161 to condense the C15 aldehyde in acetal form with ethcxyisoprene in the presence of zinc chloride, followed by the hydrolysis of the acetal with an acid and the removal of the ethoxy group.
The present invention also relates to a method for preparing for preparing vitamin A starting with xcex2-ionone.
This method consists, in a first step, in isomerizing the xcex2-ionone to retro-xcex1-ionone in the presence of potassium tert-butoxide in dimethyl sulfoxide as for example described by Cerfontain in Synthetic Communications, 1974, 4(6), 325-30. This method relates more generally to the isomerization of xcex2-ionone with a strong base chosen from alkali metal alcoholates or alkali metal hydroxides, in a polar aprotic solvent. The alkali metal alcoholate is preferably sodium methoxide; the alkali metal hydroxide is preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium or barium hydroxides. The solvent is in particular chosen from dimethyl sulfoxide, N-methylpyrrolidone or dimethylformamide. It is preferable to use a molar ratio between the strong base and the xcex2-ionone of between 1 and 1.5. As regards the reaction conditions, it is preferable to work below room temperature and preferably between xe2x88x9210xc2x0 C. and 20xc2x0 C.
The second step consists in carrying out an ethynylation cf the retro-xcex1-ionone obtained above according to the following reaction scheme: 
This step is carried out in the presence of lithium or magnesium acetylide. The use of magnesium acetylide formed in situ by bringing acetylene into contact with isopropylmagnesium chloride is preferred. As solvent, the use of ethers, polar solvents such as aromatic solvents is preferred; the use of tetrahydrofuran is most particularly preferred. The reaction temperature is preferably less than room temperature. It is in particular between xe2x88x9210xc2x0 C. and room temperature. The reaction is preferably carried out in a solvent chosen from ethers, polar solvents such as aromatic solvents; the use of tetrahydrofuran is most particularly preferred.
The ethynyl-retro-xcex1-ionol is then acetylated in accordance with the first step of the first method according to the invention, the propargyl acetate obtained is, according to the overall method for preparing vitamin A, condensed with a 1-methylbutadiene derivative according to the following reaction scheme: 
in which R represents a linear or substituted C1-C4 alkyl group, a linear or substituted C1-C4 acyl group or a trialkylsilyl or triarylsilyl group. The use of acetyl-1-methylbutadiene or 3-trimethylsilyloxy-1-methylbutadiene is preferred. The condensation reaction is preferably carried out in the presence of a Lewis acid chosen in particular from zinc chloride, titanium tetrachloride, boron trifluoride or the trityl salts (perchlorate, tetrafluoroborate). For a better implementation of the invention, the use of a solvent chosen from polar solvents such as nitroalkanes or chlorinated solvents is preferred. As regards the reaction conditions, the use of temperatures between xe2x88x9250xc2x0 C. and +20xc2x0 C., preferably between xe2x88x9230 and 0xc2x0 C., is preferred.
The derivative thus obtained, which is an isomer of vitamin A, is isomerized to vitamin A under the same conditions as above according to the following scheme: 
This reaction is carried out in the presence of an acid, in a ketone solvent or in an aromatic solvent which is in particular halogenated. The isomerization catalyst is chosen from inorganic acids such as in particular hydrochloric acid, hydrobromic acid or sulfuric acid. The use of hydrobromic acid in acetone is preferred.
According to a better way of carrying out the invention, it is preferable to use 0.25 to 0.5 equivalent of hydrobromic acid per mol of C20 allene derivative to be isomerized.
The all-trans-retinal is then obtained by rectifying with the iodine-hydroquinone complex according to U.S. Pat. No. 2,683,746.
The present invention will be described more fully with the aid of the following examples which should not be considered as limiting the invention.